Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
  • C07D451/06—Oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics

Definitions

• the present invention relates to a process for preparing substituted 8-azabicyclo[3.2.1]octan-3-ols.
• Substituted 8-azabicyclo[3.2.1]octan-3-ol compounds disclosed in U.S. Pat. No. 6,262,066 are NOP receptor agonists (previously known as ORL-1 receptor agonists) useful in the treatment of various disorders such as pain, anxiety and cough.
• ORL-1 receptor agonists previously known as ORL-1 receptor agonists
• U.S. Pat. No. 6,262,066 discloses a process for preparing the claimed compounds comprising an expensive and unstable tropinone as a starting material.
• a preferred group of 8-azabicyclo[3.2.1]octan-3-ols including 8-[bis(2-chlorophenyl)methyl]-3-pyrimidin-2-yl-8-azabicyclo[3.2.1]octan-3-ol, is specifically disclosed in U.S. Pat. No. 6,727,254.
• the multi-step process disclosed in U.S. Pat. No. 6,727,254 comprises reaction of a tropinone with a diphenylmethyl derivative, followed by reaction with a tributyltin derivative of pyrimidine and an alkyl lithium derivative.
• the present invention relates to a process for preparing compounds having the structural formula I
• R is benzyl, R 5 -benzyl, allyl, —C(O)R 6 , —C(O)OR 8 or —CH(R 7 ) 2 ;
• each R 7 is independently selected from the group consisting of R 2 -phenyl and R 2 -heteroaryl;
• R 1 is R 3 -aryl, R 3 -heteroaryl, R 3 -arylalkyl or R 3 -heteroarylalkyl;
• R 2 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy and alkoxy;
• R 3 is 1-3 substituents independently selected from the group consisting of hydrogen, halogen and alkyl;
• R 5 is 1 or 2 substituents independently selected from the group consisting of halogen, alkoxy and —NO 2 ;
• R 6 is H, alkyl, haloalkyl or benzyl
• R 8 is alkyl, benzyl or allyl
• step d) optionally recrystallizing the product of step b) or step c) to obtain a purified product.
• R b is benzyl, R 5 -benzyl, allyl, —C(O)R 6 or —C(O)OR 8 .
• R 9 is alkyl and R 1 and R 7 are as defined above for formula I, provided that R 2 is not hydroxy, comprising alkylating a compound of the formula VI
• step (c) i.e., the product of step (c).
• the process of the invention comprises preparing a compound of formula Ia
• R a is —CH(R 7 ) 2 , preferably
• each R 2 is independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy and alkoxy;
• R 1 is R 3 -aryl, R 3 -heteroaryl, R 3 -arylalkyl or R 3 -heteroarylalkyl, wherein R 3 is 1-3 substituents independently selected from the group consisting of hydrogen, halogen and alkyl;
• step b) optionally recrystallizing the product of step b) to obtain a purified product.
• the process of the invention comprises preparing a compound of formula Ia′
• R 2 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy and alkoxy;
• step b) optionally recrystallizing the product of step b) to obtain a purified product.
• the process of the invention comprises preparing compounds of formula Ia
• R a is —CH(R 7 ) 2 , preferably
• each R 2 is independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy and alkoxy;
• R 1 is R 3 -aryl, R 3 -heteroaryl, R 3 -arylalkyl or R 3 -heteroarylalkyl, wherein R 3 is 1-3 substituents independently selected from the group consisting of hydrogen, halogen and alkyl;
• R b is as define above;
• X is halogen, —OSO 2 CH 3 or —O-(p-toluenesulfonyl);
• step d) optionally recrystallizing the product of step c) to obtain a purified product.
• the process of the invention comprises preparing compounds of formula Ia′
• R 2 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy and alkoxy;
• R b is as defined above;
• X is halogen, —OSO 2 CH 3 or —O-(p-toluenesulfonyl);
• step d) optionally recrystallizing the product of step c) to obtain a purified product.
• Preferred compounds of formula I prepared by the claimed process are those wherein R is
• each R 2 is halogen, more preferably chloro, still more preferably 2-chloro, and wherein R 1 is R 3 -heteroaryl, especially pyrimidyl, and more especially 2-pyrimidyl.
• a preferred compound prepared by the claimed process has the structure I-A:
• the present process eliminates the use of nortropinone hydrochloride, an expensive and relatively unstable reagent.
• Step (b) of the present process comprising the addition of an alkyl lithium to a mixture of the tropinone of formula III and the iodo-heteroaryl, IR 1 , is a one-step procedure resulting in high yields of the compound of formula I in excellent purity.
• This process eliminates the undesirable tin chemistry used in U.S. Pat. No. 6,727,254, as well as eliminating the isolation step and difficult work-up.
• the preparation of the tropinone uses the known Robinson Schoepf synthesis, but for the preferred process of the invention, the successful addition to the ketone of an in situ formed 2-pyrimidyl anion, known in the literature to be unstable, is unexpected.
• the present process is easier to perform than the procedures in the art, and provides the product in higher yield.
• step (a) the reaction is carried out in a solvent and a buffer.
• the solvent is water or a water miscible organic solvent such as N-methylpyrrolidine (NMP), dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, or an alcohol such as isopropanol, or a mixture thereof, optionally in the presence of a base such as NaOH (aqueous solution), triethylamine (Et 3 N) or NaHCO 3 .
• the buffer is an aqueous buffer wherein the buffering agent is, for example sodium acetate, sodium citrate or disodium hydrogenphosphate and the pH is acidified with an acid such as HCl, preferably to a pH of about 2 to about 6.
• the reaction is carried out over a temperature of about 0° C. to about 60° C., most preferably starting at about 0-5° C., then increasing gradually to about 50° C.
• the concentration of reactants in step (a) can vary in a range of about +/ ⁇ 20%.
• the amount of 2,5-dimethoxytetrahydrofuran can range from 1.1 to 1.35 equivalents and the amount of acetone dicarboxylic acid (or ester thereof) or HC(O)(CH 2 ) 2 C(O)H can vary from 1.1 to 2 equivalents; the amount of HCl can vary from 0.1 to 1.5 equivalents, and the amount of sodium acetate or other buffering agent can vary from 1 to 4 equivalents.
• step (b) the reaction is carried out in a solvent such as THF, toluene, DME, THF/n-hexane, THF/n-heptane or a mixture thereof.
• concentration can vary from about 10 ⁇ solvent to 30 ⁇ solvent, with the concentration of I-R 1 being 1 to 5 equivalents, preferably 1 to 2 equivalents.
• the reaction is carried out in a temperature range of about ⁇ 20° C. to about ⁇ 100° C., preferably at about ⁇ 60° C. to about ⁇ 100° C.
• the alkyl lithium is, for example n-butyl lithium, sec butyl lithium, tert. butyl lithium or n-hexyl lithium, present in a range of 1 to 2.5 equivalents.
• N-hexyl lithium has the advantage of not generating a gas when the reaction is quenched.
• the alkyl lithium can be added as the last reagent, or it can be added simultaneously with I-R 1 .
• the lithium salt is, for example, LiBr, LiCl, lithium acetate or lithium tosylate.
• concentration of lithium salt can vary from 0 equivalents to about 5 equivalents; preferably, it is present in a concentration of about 2.5 equivalents.
• the presence of the lithium salt improves the yield and purity of the product.
• the addition of the lithium salt increases the stability of the lithium pyrimidine species generated in situ by the addition of alkyl lithium to the iodopyrimidine. When used in the reaction, the lithium salt is added to I-R 1 before the alkyl lithium.
• step (c)(i) the conversion of a compound wherein R is benzyl, R 5 -benzyl, allyl, —C(O)R 6 or —C(O)OR 8 to a compound wherein R is —CH(R 7 ) 2 is achieved by removing the nitrogen protecting group to obtain a compound of formula I(c)(i) or a salt thereof, using methods well known in the art.
• the R group can be removed by reaction with a palladium catalyst. Typical procedures include hydrogenation with palladium on charcoal or reaction with tetrakis(triphenyl-phosphine)palladium, preferably in the presence of N,N-dimethyl barbituric acid.
• a salt is of formula I(c)(i) is desired, e.g., an HCl or N,N-dimethyl barbituric salt
• the salt is prepared after removal of the R group or in situ during the deprotection reaction.
• step (c)(ii) the compound of formula IV is reacted with the free base or salt of formula I(c)(i) at elevated temperatures in an organic solvent such as acetonitrile, in the presence of a base such as K 2 CO 3 .
• step (d) of the product of step (b) or (c) is carried out using standard techniques, for example the crude product is dissolved in a heated organic solvent such as alcohol or an acetone/alcohol mixture, the resultant mixture is filtered, and then cooled (with seeding if necessary) to obtain the crystalline product.
• a heated organic solvent such as alcohol or an acetone/alcohol mixture
• Alkylation of the product of step (c), i.e. a compound of formula VI, to obtain a compound of formula V is achieved by methods well known in the art, for example by reaction of the product of step (c) with an alkyl iodide, e.g., methyl iodide, in the presence of a base.
• an alkyl iodide e.g., methyl iodide
• steps (a) to (d) are preferably carried out in an inert atmosphere, e.g., under nitrogen.
• alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
• Haloalkyl means an alkyl groups as defined above substituted by 1-3 halogen atoms.
• Alkoxy means an alkyl-O— group in which the alkyl group is as previously described.
• suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.
• the bond to the parent moiety is through the ether oxygen.
• Aryl means phenyl or naphthyl.
• R 3 -aryl refers to such groups wherein substitutable ring carbon atoms have an R 3 substituent as defined above.
• Heteroaryl means a single ring, bicyclic or benzofused heteroaromatic group of 5 to 10 atoms comprised of 2 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, provided that the rings do not include adjacent oxygen and/or sulfur atoms. N-oxides of the ring nitrogens are also included.
• single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl.
• bicyclic heteroaryl groups are naphthyridyl (e.g., 1,5 or 1,7), imidazopyridyl, pyrido[2,3]imidazolyl, pyridopyrimidinyl and 7-azaindolyl.
• benzofused heteroaryl groups are indolyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl (i.e., thionaphthenyl), benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl.
• R 3 -heteroaryl refers to such groups wherein substitutable ring carbon atoms have an R 3 substituent as defined above.
• Halogen means a fluoro, chloro, bromo or iodo atom.
• Solvate means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
• Certain compounds of the invention may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers).
• the invention contemplates all such stereoisomers both in pure form and in mixture, including racemic mixtures.
• Certain compounds will be acidic in nature, e.g. those compounds which possess a phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
• Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts.
• pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids.
• suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art.
• the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
• the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
• a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
• the free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
• Ms methylsulfonyl
• Me methyl
• EtOAc ethyl acetate
• LOD loss on drying
• DMAP 4-dimethylamino-pyridine
• TBME tert-butyl methyl ether
• DMSO dimethyl sulfoxide
• gas chromatography GC
• HPLC high performance liquid chromatography
• 1,1′-(bromomethylene)bis(2-chlorobenzene) (110 g, 0.35 mol) was dissolved in CH 3 CN (550 ml) at 20 to 25° C. Over 30 min, gaseous ammonia (28.5 g, 1.7 mol) was passed into the solution at 20 to 25° C. (slight cooling is necessary). The mixture was heated in an autoclave to 93 to 96° C. for 3 h at a pressure of 6 bar. The mixture was stirred at 93 to 96° C. and the reaction was followed by HPLC. After complete reaction (10 to 14 h), the mixture was cooled to 20-25° C. and degassed. The suspension was concentrated under vacuum at 45 to 50° C.
• the mixture was stirred at ⁇ 95 ⁇ 5° C. and the reaction was followed by HPLC. After complete reaction (20 to 30 min), the mixture was warmed up to ⁇ 50 to ⁇ 30° C. over 75 min and added over 10 min to a solution of NH 4 Cl in water (19.8 g in 290 ml) at 20 to 25° C. The mixture was warmed up to 20 to 25° C. and the phases were separated. The organic layer was washed with a solution of NaCl in water (23.2 g in 200 ml). The organic layer was concentrated under vacuum at 50° C. to a volume of 240 ml. To the resultant suspension, n-heptane (865 ml) was added, 400 ml were evaporated under vacuum at 50° C.
• Step (b) The synthesis is done according to the procedure of Example 1, Step (b), starting with the crude product of Step (a) (110 g). After washing with brine, the product was isolated by evaporation of the organic phase in vacuum to dryness at 50° C. The residue was diluted with isopropanol (425 ml) and heated to reflux. After filtration, the solution is cooled to ⁇ 15 to ⁇ 10° C. and stirred for 60 min. The product is filtered off, washed with isopropanol (50 ml) and dried to constant weight under vacuum and a slight stream of N 2 at 50° C. Yield: 100 g (74%). Assay (HPLC): 100% pure vs. standard.
• Step (b) the product of Step (b) (18.0 g, 61 mmol) was dissolved in 1,2-dichloroethane (180 ml) at 0 to 5° C. Over 5 min, 1-chloroethyl chloroformate (10 ml, 92 mmol) was added and the mixture was slowly warmed to 20-25° C. over 100 min. The mixture was then heated to 80-85° C. and the reaction was followed by HPLC. After complete reaction (2 to 4 h), the mixture was cooled to 50° C. and evaporated to dryness under vacuum. At 60 to 65° C., methanol (90 ml) was added and the mixture was stirred for 40 min until evolution of CO 2 ceased.
• Step (c) the crude product of Step (c) (4.9 g, 10.8 mmol) was dissolved in boiling isopropanol (100 ml). The hot mixture was filtered, cooled slowly to 0 to 5° C. and stirred for another 90 min. The product was filtered off, washed with isopropanol (10 ml) and dried under vacuum at 50° C. to constant weight. Yield: 4.4 g (93% abs.). Assay (HPLC): 99.8% pure vs. standard.
• Step (c)(ii) Using a procedure similar to that in Example 2, Step (c)(ii), with the product of Step (c)(i) (4.5 g, 12.5 mmol) as the starting material, the desired product was obtained. Yield: 5.2 g (90% abs.). Assay (HPLC): 95% pure vs. standard.

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• 2005
  • 2005-09-13 CA CA002580292A patent/CA2580292A1/en not_active Abandoned
  • 2005-09-13 EP EP05797864A patent/EP1791838A2/en not_active Withdrawn
  • 2005-09-13 US US11/225,244 patent/US7459556B2/en not_active Expired - Fee Related
  • 2005-09-13 JP JP2007531447A patent/JP2008513368A/ja not_active Withdrawn
  • 2005-09-13 WO PCT/US2005/032512 patent/WO2006031788A2/en active Application Filing
  • 2005-09-13 MX MX2007003061A patent/MX2007003061A/es active IP Right Grant
  • 2005-09-13 AR ARP050103818A patent/AR053527A1/es not_active Application Discontinuation
  • 2005-09-13 CN CN200580038161A patent/CN100577661C/zh not_active Expired - Fee Related
• 2007
  • 2007-03-09 ZA ZA200702070A patent/ZA200702070B/xx unknown

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